The PI3K/AKT/mTOR signalling pathway is one of the most frequently activated pathways in breast cancer and also plays a central role in the regulation of several physiologic functions. There are major efforts ongoing to exploit precision medicine by developing inhibitors that target the three kinases (PI3K, AKT, and mTOR). Although multiple compounds have been developed, at present, there are just three inhibitors approved to target this pathway in patients with advanced ER-positive, HER2-negative breast cancer: everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor). Like most targeted cancer drugs, resistance poses a major problem in the clinical setting and is a factor that has frequently limited the overall efficacy of these agents. Drug resistance can be categorised into intrinsic or acquired resistance depending on the timeframe it has developed within. Whereas intrinsic resistance exists prior to a specific treatment, acquired resistance is induced by a therapy. The majority of patients with ER-positive, HER2-negative advanced breast cancer will likely be offered an inhibitor of the PI3K/AKT/mTOR pathway at some point in their cancer journey, with the options available depending on the approval criteria in place and the cancer’s mutation status. Within this large cohort of patients, it is likely that most will develop resistance at some point, which makes this an area of interest and an unmet need at present. Herein, we review the common mechanisms of resistance to agents that target the PI3K/AKT/mTOR signalling pathway, elaborate on current management approaches, and discuss ongoing clinical trials attempting to mitigate this significant issue. We highlight the need for additional studies into AKT1 inhibitor resistance in particular.
PI3K/AKT/mTOR信号通路是乳腺癌中最常被激活的通路之一，同时在多种生理功能的调控中发挥核心作用。目前通过开发靶向三种激酶（PI3K、AKT和mTOR）的抑制剂来实现精准医疗已成为重要研究方向。尽管已开发出多种化合物，但目前仅有三款抑制剂获批用于治疗晚期ER阳性、HER2阴性乳腺癌患者：依维莫司（mTOR抑制剂）、阿培利司（PIK3CA抑制剂）和卡皮瓦塞替（AKT抑制剂）。与大多数靶向抗癌药物类似，耐药性在临床实践中构成主要挑战，也是限制这些药物整体疗效的关键因素。根据发生时间，耐药性可分为固有耐药和获得性耐药：固有耐药存在于特定治疗前，而获得性耐药则由治疗诱发。多数ER阳性、HER2阴性晚期乳腺癌患者在病程中可能接受PI3K/AKT/mTOR通路抑制剂治疗，具体方案取决于现行批准标准及肿瘤突变状态。在这一庞大患者群体中，多数人可能在治疗过程中出现耐药，这使得该领域成为当前的研究热点和未满足的临床需求。本文系统综述了靶向PI3K/AKT/mTOR信号通路药物的常见耐药机制，详述当前临床应对策略，并探讨旨在解决这一重大问题的临床试验进展。我们特别强调需要加强对AKT1抑制剂耐药机制的深入研究。
肿瘤(癌症)患者之家